CZ50596A3 - Alkoxy substituted beta-carbolines, process of their preparation, their use and medicaments containing thereof - Google Patents

Abstract

Compounds having the formula (I) are disclosed, as well as their preparation and use in medicaments acting on the AMPA-receptor.

Description

Technical field

The invention relates to novel derivatives. alkoxy-β-carbol-in-i --------------- processes for their preparation, their use in pharmaceuticals, pharmaceutical compositions containing them, and intermediates for the manufacture of these derivatives.

BACKGROUND OF THE INVENTION

It is known from numerous publications that β-carbolines have an affinity for benzodiazepine receptors and can be used as psychopharmaceuticals on the basis of this affinity for benzodiazepine receptors.

SUMMARY OF THE INVENTION

It has now surprisingly been found that the compounds of formula I below act on the modulating sites of the MPA receptor or on the AMPA receptor-dependent ion channels and correct pathologically altered function of this receptor. The synaptic function of the excitatory amino acid L-glutamate is predominantly mediated via AMPA receptors. Increased or decreased glutamate neurotransmission in the central nervous system leads to numerous neurological and *

psychiatric disease. The compounds of formula (I) below are thus suitable for the manufacture of a medicament for the sympathetic and preventive treatment of neurological and psychiatric diseases.

. Accordingly, the present invention provides alkoxy-substituted β-carboline derivatives of formula (I)

A denotes a straight or branched alkylene group having up to 5 carbon atoms which may be substituted by a hydroxy group, an alkoxy group having 1 to 6 carbon atoms or an alkanoyloxy group having 1 to 6 carbon atoms, or a group - (CH ₂ ) _n -CO- (CH ₂ ) _m -, where

AND.

n and m are 1, 2 or 3,

R ¹ and R 2 are the same or different and are hydrogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 9 cycloalkyl, phenyl, phenylalkyl Or (C 1 -C 2) alkyl;

9

R 1 and R 2 together with the nitrogen atom form a heterocycle of formula (a) wherein: (a) wherein:

Β denotes a direct bond, an oxygen atom, a sulfur atom or a group -CH-R 6, = CQH-R 6 or = N-R 6, wherein R 5 denotes a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a group

or optionally a C 1 -C 6 alkyl group, an alkoxy group

1-4 carbon atoms, halogen, hydroxy, trifluoromethyl or -O-CF3 substituted by one to three times phenyl, benzyl, benzoyl, α-hydroxybenzyl, phenethyl, 2-oxo-2-phenethyl, 1-oxo-2-phenethyl or a pyridine group α

Y represents an oxygen atom, a sulfur atom or a group = NH, *

R ^ represents a hydrogen atom, a carboxyl group, a COO-alkyl group having 1 to 6 carbon atoms in the alkyl group, a CO-R R group or, optionally, one to three times an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms halogen, alkoxyalkyl of 1 to 4 carbon atoms in alkoxy and 1 to 2 carbon atoms in alkyl, alkoxy of 1 to 4 carbon atoms, phenyl or amino substituted aryl of 6 to 12 carbon atoms or heteroaryl, wherein (C až-C) alkyl, (C až-C cyk) cycloalkyl, (C až-C bic) bicycloalkyl, or optionally (C až-C alky) alkyl, (C 4-C alko) alkoxy or mono-cyclic or bicyclic-substituted amino an aryl group having 6 to 12 carbon atoms denotes a hydrogen atom, an alkyl group (C 1 -C 6) or (C 1 -C 4) alkoxyalkyl (C 1 -C 2) alkyl; and

R ^ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenylalkyl group having 1 to 2 carbon atoms, an optionally substituted benzenesulfonyl group or an alkanesulfonyl group having an alkyl group;

up to 4 carbon atoms, k

as well as their stereoisomers and salts.

When the compounds of formula I have chiral centers, the present invention includes all possible stereoisomers, as well as enantiomers and diastereomers, as well as mixtures and racemates thereof.

The substituent in the A-ring may be in the 5- to 8-position, preferably-5-or-6 -...

A straight or branched alkylene group having 1 to 5 carbon atoms is, for example, methylene, ethylene, propylene, isopropylidene,

1-methylethylene, 2-ethylpropylene,

2,2-dimethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene and tetramethylene. The substituent of the alkylene radical A is in any position, preferably in the 2-, 3- or 4-position of the straight alkylene radical. and

Alkyl groups include both straight and branched groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl , hexyl, 2,2-dimethylpropyl- and 2-methylbutyl.

Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

2-methyl-cyclopropyl.

Cycloalkylalkyl radicals include cyclopropylmethyl and cyclohexylmethyl.

The phenylalkyl substituent having 1 to 2 carbon atoms in the alkyl may be straight or branched in the alkyl moiety, such as, for example, benzyl, phenexyl or α-mexylbenzyl.

Possible halogen are fluorine, chlorine, bromine and iodine.

--- Pyridine. it is bound to position 2, 3 or 4.

The aryl or hexeroaryl moiety can be oxidized as a monocycle or a bicyclic ring and contains 5 to 12 axomes in the ring, preferably 5 to 9 atoms. Examples which may be mentioned are phenyl, biphenyl, naphthyl and indenyl such as aryl and thienyl. . pin, furyl, pyranyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, Xhiazolyl, isoxhiazolyl, 1,3,4-oxadiazol-2-yl group

1,2.4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, quinolyl, isoquinolyl, benzo [1] xhienyl or benzofuryl as heteroaryl residues with 1 to 3 hexeroatoms such as is sulfur, oxygen and / or nitrogen. * ť <

Preferred hexeroaryl radicals R include isoxazol-3-yl, isoxazol-5-yl, 1,2,4-oxadiazol-5-yl,

1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, xhiazol-4-yl, Xhiazol-2-yl, pyrrol-2-yl, pyrrol-3-yl, 2-xhienyl, 3-Xhenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl and oxazol-5-yl, which may be optionally sub-mixed. A preferred aryl R is a phenyl group optionally substituted by a halogen or alkoxy group having 1 to 4 carbon atoms.

The term bicycloalkyl radical R (R) refers to a bicycloheptyl group and a bicyclooctyl group, such as. a monocyclic or bicyclic aryl radical R1 is, for example, phenyl, biphenyl, naphthyl and indenyl.

The (C 1 -C 6) alkanoyl moiety is derived from straight or branched aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, trimethylacetic acid or caproic acid.

Suitable sulfonic acid radicals R ^y are the well-known behenesulfonic acids which may be substituted by halogen or an alkyl group having 1 to 4 carbon atoms, as well as alkanesulfonic acids having 1 to 4 carbon atoms, such as methanesulfonic acid and p-toluenesulfonic acid.

-ϋΡ

Physiologically acceptable salts are derived from inorganic and organic acids such as hydrohalic acids, for example hydrochloric and hydrobromic acid, sulfuric acid or phosphoric acid;

organic acids, for example aliphatic or aromatic monocarboxylic or dicarboxylic acids, such as formic acid, acetic acid, maleic acid, fumaric acid, glutaric acid, lactic acid, tartaric acid, citric acid, oxalic acid and glyoxylic acid, or sulfonic acids, such as alkanesulfonic acid acids with 1 to 4 carbon atoms such as methanesulfonic acid or optionally halogenated or alkyl substituted benzenesulfonic acids such as p-toluenesulfonic acid.

Preferred are compounds of formula I wherein:

R ¹ and R ² together with the nitrogen atom form a heterocycle of formula (a) *

(and)

Wherein B is as defined above, represents a hydrogen atom, a carboxyl group, a COO-alkyl group having 1 to 6 carbon atoms in the alkyl, or optionally one to three times an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 C 1 -C 4 -alkoxy, halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxyalkyl, C 1 -C 2 -alkyl, phenyl or C 6 -C 12 -alkyl-substituted aryl atoms or heteroaryl group;

and R ⁴ , and A are as defined above.

Particularly preferred are compounds of formula I wherein:. *

A denotes a straight or branched alkylene group having 1 to 5 carbon atoms, which may be substituted by a hydroxy or alkoxy group having 1 to 6 carbon atoms,

12 »»

R and R together with the nitrogen atom form a heterocycle. formula r ~ \

(a) ---- in which B is as defined above,

R ^ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms and

IN

R ^ represents a hydrogen atom, a carboxyl group or a COO-alkyl group having 1 to 6 carbon atoms in the alkyl, and stereoisomers and salts thereof.

When R znamená represents a phenyl, benzyl, benzoyl, α-hydroxybenzyl, phenethyl, 2-oxo-2-phenethyl or 1-oxo-2-phenethyl group which is substituted, it is to be regarded as a substituent as a preferred halogen and alkoxy group with 1-4 carbon atoms, in particular a fluorine-substituted radical, substitution at the 4-position being preferred.

The present invention further relates to a process for the preparation of alkoxysubstituted β-carbolines of the general formula I, which comprises:

a) a compound of formula II

in which · they have i____R ³ , JI ⁴ . and R ^y . the above meaning is reacted with an amine of formula III

X — A — N

R ¹ (lil)

R 2 - in which R ^X , * R ^2a , A have the above meanings and m X is a leaving group, or +

*: ·

b) a compound of formula IV

in which A, R ³ , R ⁴ and R ^{9 are} as defined above and X denotes a leaving group, ♦ reacts with an amine of formula V

H-N

R1

(V)> 12 in which R and R are as hereinbefore defined, and optionally the substituent is then introduced or cleaved, if desired, or a physiologically acceptable salt is formed, or the physiologically acceptable salt is converted into the free compounds of formula I, or racemates,

The nucleophilic substitution of the leaving group X according to variants a) and b) is carried out by conventional methods in organic solvents / inert under the reaction conditions, under basic conditions.

*

Suitable leaving groups X are halogens such as chlorine, bromine or iodine, or organic sulfonic acid residues such as alkanesulfonic acid residues such as mesylate and triflate or aromatic sulfonic acid residues such as toluenesulfonic acid or bromobenzenesulfonic acids.

Suitable inert organic solvents are polar solvents such as dimethylformamide, dimethylacetamide, alcohols such as ethanol or methanol, cyclic ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons or aromatic hydrocarbons, and mixtures of the solvents mentioned.

Suitable bases are inorganic and organic bases. Examples of inorganic bases are alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates or alcoholates. Examples of organic bases include tertiary organic amines such as tripropylamine, triethylamine, N-alkylmorpholines or N-alkylpiperidines. However, an excess of the amine of the general formula may be used as the base. The reaction may be carried out in the presence of phase transfer catalysts.

and'

The reaction temperatures may range from 0 ° C to the boiling point of the solvent used.

*

The introduction of the substituent can be carried out by customary alkylation, benzylation or sulfobenzylation processes, for example by reacting a substituent of a substituent. R 1 is reacted with carboline in the presence of a base.

Cleavage of the substituent is carried out by conventional methods, depending on the type of substituent-base or hydro-genolytic. ^{= = J =}

The compounds of formula 1 can be isolated and purified from the reaction mixture by known methods. The acid addition salts may be converted into the free bases by conventional means and converted into physiologically acceptable acid addition salts by conventional methods, for example by mixing the solution with a concentrated solution of the desired acid. ’;

If the compounds of formula I contain chiral centers, the optically active compounds can be obtained starting from optically active starting compounds or obtained from racemates in a manner known per se. Separation of the enantiomers may be carried out, for example, by chromatography on optically active supports or by reaction with optically active acids followed by fractionated crystallization.

t,.

' .her ' '

to.

The present invention also relates to novel compounds of the general formula IV-

The starting compounds of formula (IV) are valuable products for the preparation of pharmacologically active compounds, for example of the compounds of formula (I).

The preparation of the compounds of the general formula (IV) is carried out by methods known per se, for example by:

a) a compound of formula II

in which R @ 1 and R @ 2 are as hereinbefore defined, etherify with a compound of formula VI

X - A - Y (VI) wherein A and X are as defined above and Y is a cleavable group, or

(b) the compound of formula (II) is etherified with an alcohol of formula (VII)

Y-A-OH (VII) in which Y is as defined above and then is cleaved off. groups on. X ... _, ____________ ..... ...........

Suitable leaving groups are those mentioned for substituent X. Etherification is carried out in a conventional manner in the presence of a base. The introduction of the leaving group X is carried out by conventional methods.

If the preparation of the starting compounds is not described, they are known or can be produced analogously to known compounds or by the methods described herein.

For example, the hydroxy derivatives of the formula II can be prepared according to EP-A 130 140, EP 0 161 574, EP 0 305 322, WO 92/21 697 and WO 92/22 549.

The compounds of the formula I as well as their physiologically acceptable salts are useful as medicaments by virtue of their action on the quisqualate receptor or qursqualate receptor-dependent ion channel modulation sites.

The pharmacological activity of the compounds of formula I is determined by the following test.

Male NMRI-mice weighing 18-22 g are maintained under controlled conditions (6θθ-18θθ light / dark rhythm, with free food and water availability) and divided into groups. Groups consist of 5 to 16 animals. Observations of the animals shall be made between 8 ° and 13 °.

AMPA is injected into the left ventricle of the freely movable ýγδΐ ”. The applicator consists of a cannula with a stainless steel device that limits the injection depth to 3.2 mm. The applicator is connected to a syringe pump. The injection needle is inserted perpendicular to the surface. skull— by-coordinate- -

Montemurry and Dukelowa. The animals are observed until clonic. or tonic seizures up to 180 seconds. Clonic movements that last longer than 5 seconds count as cramps. The onset of clonic seizures is used as the endpoint for determining the seizure threshold. The dose required to increase or decrease the convulsion threshold by 50% m (THRD?) Is determined in 4-5 experiments. The values of ^ THRD ^ q and the confidence limits are determined by regression analysis.

and

The results of these experiments show that the compounds of formula I and their acid addition salts affect functional disorders of the AMPA receptor. They are therefore suitable for the manufacture of medicaments for the symptomatic and preventive treatment of diseases which are caused by a change in the function of the AMPA receptor complex.

Treatment with the compounds of the present invention suppresses or reduces cell damage and functional disorders due to the disease and thereby reduces the symptoms induced.

Diseases that may be caused by dysfunction of excitatory amino acids or altered glutamate neurotransmission include, for example, neurodegenerative disease, such as Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, senile dementia, multiinfarkx dementia, amyotropic lateral sclerosis, degenerative sclerosis, oliver sclerosis, oliver; cell damage by hypoglycemia, hypoxia, ischemia and energy metabolism disorders; neuronal damage caused by brain damage, such as stroke, brain trauma and asphyxia, as well as psychoses, schizophrenia, "states of fear." conditions.,., pain, migraines and__________ emesis. Functional disorders such as memory disorders (amnesia), learning process disorders, manifestations of vigilance and manifestations of rejection after chronic substance abuse such as sedative drugs, hallucinogens, alcohol, cocaine and opi ₊ , r ^ν are also based on glutarate neurotransmission. ιΎτΛ »ť -_. W -ΙΓ * · * *» ··· Γ 4 -lil— ϊ μ. Λ X ates. Indications can be shown by conventional pharmacological tests.

The present invention also relates to pharmaceutical compositions comprising said compounds, their production and the use of the compounds of the present invention for the manufacture of medicaments which can be used for the treatment and prophylaxis of the aforementioned diseases. The medicaments are prepared in a manner known per se by converting the active ingredient with suitable carriers, excipients and / or additives into a pharmaceutical preparation suitable for enteral or parenteral administration. Administration can be carried out orally or sub-lingually as a solid in the form of capsules or tablets, or as a liquid in the form of solutions, suspensions, elixirs or emulsions, or rectally as suppositories, or in the form of optionally also subcutaneous injectable solutions. Suitable excipients for the desired pharmaceutical preparations are inert organic and inorganic carriers known to those skilled in the art, such as water, gelatin, acacia, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyethylene glycols and the like. If desired, preservatives, stabilizers, wetting agents, emulsifiers or salts for varying the osmotic pressure or buffers may also be present. ...........

The pharmaceutical preparations can be present in solid form, eg as tablets, dragees, suppositories, capsules, or in liquid form jako_.r.oztoky., - or suspense--emulsion ^-.

Surfactant adjuvants such as bile salts or animal or plant phospholipids, but also mixtures thereof, as well as liposomes or components thereof may also be used as carrier systems.

Tablets, coated tablets or capsules containing talc and / or hydrocarbon carriers are particularly suitable for oral administration.

or a binder such as lactose and corn;

potato starch. The application can also be carried out in liquid form, for example as a juice to which a sweetener is optionally added.

Injectable solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral administration.

The dosage of the active compounds may vary depending on the type, application, age and weight of the patient, the type and severity of the disease to be treated and the like. The daily dose may be administered as a single dose per day, or divided into two or more daily doses. The active compounds are administered in an amount of 0.05 to 500 mg of active substance in a physiologically acceptable carrier. In general, the dose is 0.1 to 1000 mg / day (0.001 to 10 mg / kg), preferably 0.1 to 100 mg / day.

The following examples serve to illustrate the preparation of the compounds of formula I.

Examples of the invention,

Example 1

5- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester

628 mg of 5-hydroxy-4-methoxymethyl-prcarboline-; 3-carboxylic acid isopropyl ester are introduced into 100 ml of acetone, mixed with 600 mg of potassium carbonate and 760 mg of (4-fluorophenyl) - [1- (3-methylsulfonyloxypropyl) - Of 4-piperidyl] ketone and the reaction mixture is heated to reflux for 3 hours under an argon atmosphere. After concentration, the organic phase is chromatographed on silica gel using acetone / hexane 1: 1. The desired fractions are concentrated and triturated with diethyl ether. 630 mg of 5- {3- [4- (4-fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-methoxymethyl-p-carboline-3-carboxylate isopropyl ester is obtained. 'Love, m.p. 161 ^DEG-162-C' (4-fluorophenyl) - [1- (3-methylsulfonyloxypropyl) -4-piperidyl] -ketone is obtained assistance- known in the literature by alkylation of 4- (4-fluorobenzoyl) - piperidine with 3-bromo-1-propanol and potassium carbonate in dimethylformamide followed by reaction with methanesulfonic acid and triethylamine in methylene chloride.

6- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy] -4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is prepared in an analogous manner.

m.p. 153-155 ° C 5- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] propoxy} isopropyl ester}. 178 DEG-180 DEG C. 5- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -isopropyl ester-4-ethyl-β-carboxylic acid 3-carboxylic acid; 4-methyl-p-carboline-3-carboxylic acid, m.p.

168-170 ° C h

5- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -β-carboline-3-carboxylic acid isopropyl ester, m.p. 182 DEG-184 DEG C. 6- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -β-carboline-3-carboxylic acid isopropyl ester,

5- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-methoxymethyl-β-carboline

6- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-methoxymethyl-β-carboline

5- {3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -4-ethyl-β-carboline

6- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-methyl-β-carboline

5- (3- [4- (4-Fluorobenzoyl) -piperidine-1-isopropyl) 5- {3- [4- (4-fluorobenzoyl) -piperidin-1-yl] -propoxy} -β-carboline-isopropyl ester yl] -propoxy} -4-roethoxymethyl-9-methyl-p-carboline-3-carboxylic acid, mp 115-117 ° C 6- {3- [4- (4-fluorobenzoyl) -piperidin-1-yl] - propoxy} -4-methoxymethyl-9-methyl-p-carboline-3-carboxyl, mp 110-111 ° C

5- (3- (4- (4-fluorobenzoyl) -piperidin-1-yl) -propoxy} -4-methoxymethyl-9-methyl-p-carboline

6- (3- (4- (4-fluorobenzoyl) -4-piperidin-1-yl) -propoxy-4-methoxylmethyl-9-methyl-p-carboline.

Example 2

AND

5- (3- [4-Phenyl-piperazin-1-yl] -propoxy} -4-methoxy-ethyl-p-carboline-3-carboxylic acid isopropyl ester.

450 mg of 5- (3-chloropropoxy) -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester were stirred with 245 mg of 4-phenylpiperazine and 0.21 ml of triethylamine in 20 ml of dimethylformamide; at a bath temperature of 100 ° C for 18 hours under an argon atmosphere. After distilling off the solvent, the residue is taken up in methylene chloride and washed once with water and once with saturated sodium chloride solution. The organic phase is dried, filtered and concentrated. The residue is chromatographed on silica gel with ethyl acetate. 420 mg of 5- (3- (4-phenyl-piperazin-1-yl) -propoxy} -4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, m.p. 176-177 ° C, are obtained.

The required 5- (3-chloropropoxy) -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester (melting point 178-180 ° C) is obtained by etherification of 5-hydroxy-4-methoxymethyl-p-carboline isopropyl ester -3-carboxylic acid 1-bromo-3-chloropropane and potassium carbonate in dimethylformamide.

Following the procedure of Example 2, the following compounds were prepared from 5- (3-chloropropoxy) -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester and a secondary amine:

5- {3- [4-Benzyl-piperazin-1-yl] -propoxy} -4-methoxymethyl-4-carboline-3-carboxylic acid isopropyl ester, mp 112-114 ° C 5- {3- [Morpholin-1-isopropyl ester -yl] -propoxy} -4-methoxymethyl-β-carboline-3-carboxylic acid, mp 112-114 ° C ⁴ 5- {3- [4- (3,4,5-trimethoxyphenyl) -piperazine-1-] - isopropyl ester yl] -propoxy} -4-methoxymethyl-β-carboline-3-carboxylic acid, mp 135-136 ° C 5- {3- [4- (4-fluorobenzyl) -piperidin-1-yl] -propoxy} - isopropyl ester - 4-methoxymethyl-O-carboline-3-carboxylic acid, mp 126-128 ° C 5r {3- [4- (4-fluoro-α-hydroxybisyl) piperidin-1-yl] propoxy} -4-methoxymethyl-4-isopropyl ester carboline-3-carboxylic acid, mp 110-115 ° C 5- {3- [4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl] propoxy} -4-methoxymethyl-p-carbolin-3- isopropyl ester 5- {3- [4-Benzoyl-piperidin-1-yl] -propoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester, mp 133-135 ° C 5- {3- [4- (4-fluorophenethyl) -

piperidin-1-yl] -propoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid 5- {3- [4- (2-oxo-2- (4-fluorophenethyl) piperidin-1-yl)] - Propoxy} -4-methoxyinethyl-p-carboline-3-carboxylic acid 5- <3- [4- (1-oxo-2- (4-fluorophenethyl) piperidin-1-yl) -propoxy} -4-methoxymethyl-p-isopropyl ester -carboline-3-carboxylic acid

Example#

5- {4- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -butoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester

520 mg of 5- (4-chlorobutoxy) -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester (m.p. 147-148 ° C) and 411 mg of 4- (4-fluorobenzoyl) -piperidine are obtained in an analogous manner to that described in Example 2 235 mg of 5- {4- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -butoxy} -4-methoxy-methyl-p-carboline-3-carboxylic acid isopropyl ester, m.p. 103-105 ° C. .__..______

The following are produced in an analogous manner:

6- {4- [4- (4- (4-fluorobenzoyl) -piperidin-1-yl] -butoxy} -4-methoxymethyl) - beta -carboline-3-carboxylic acid isopropyl ester 5- {4- [4- (4-Fluoro-α-hydroxybenzyl) -piperidin-1-yl] -butoxy} -4-methyl-4-carboline-3-carboxylic acid

5- {4- [4- (4-Fluoro-α-hydroxybenzyl) -piperidin-1-yl] -butoxy} -4-methoxymethyl-β-carboline.

Example 5

5- {2- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -ethoxy} -4-methoxymethyl-4-carboline-3-carboxylic acid isopropyl ester

From 510 mg of 5- (4-chloroethoxy) -4-methoxymethyl-4-carbonyl-3-carboxylic acid isopropyl ester (m.p. 194-195 ° C) and 311 mg of 4- (4-fluorobenzoyl) -piperidine were obtained in analogy to the procedure described in Example 2195 mg of 5- {2- [4- (4-fluorobenzoyl) -piperidin-1-yl] -ethoxy} -4-methoxymethyl-4-carboline-3-carboxylic acid isopropyl ester, m.p. 161-163 ° C.

The following are produced in an analogous manner:

6- (2- [4- (4-Fluorobenzoyl) -piperidine24) isopropyl ester

-1-yl] -ethoxy) -4-methoxymethyl-β-carboline-3-carboxylic acid f

5- {2- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -ethoxy} -4-methoxy-methyl-β-carboline

5- {2- [4- (4-Fluoro-α-hydroxybenzyl) -piperidin-1-yl] -ethoxy} -4-methoxymethyl-β-carboline.

Examples

5- {3- [4- (4-Fluorobenzoyl) -piperidino] -2-hydroxypropoxy} -4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester

700 mg of 4-methoxymethyl-5- (2,3-epoxypropoxy) -4-carboline-3-carboxylic acid isopropyl ester are dissolved in 50 ml of 2-propanol and treated with 380 mg of 4- (4-fluorobenzoyl) piperidine. After refluxing for 5 hours under an argon atmosphere, the organic phase is concentrated and the residue is chromatographed on silica gel with methylene chloride / ethanol 100:50.

655 mg of 5- {3- [4- (4-fluorobenzoyl) -piperidino] -2-hydroxypropoxy} -4-methoxy isopropyl ester is obtained _; methyl-β-carboline / β-carboxylic acid. with melting point. 143 ° (Ζ>.

- - - ’

V · ^> '''. · <' · · Í

4-Methoxymethyl-5- (2,3-epoxypropoxy) -4-carboline-3-carboxylic acid isopropyl ester is obtained according to methods known in the literature by etherification of 5-hydroxy-4-methoxymethyl-4-carbonyl-3-carboxylic acid isopropyl ester with epichlorohydrin and potassium carbonate in dimethylformamide.

In an analogous manner, 5- {3- [4- (4-fluorobenzoyl) -piperidino-2-hydroxypropoxy} -4-ethyl-p-carboline-3-carboxylic acid isopropyl ester is obtained, m.p.

119 to Ϊ29 ° N ...... .........

5- {3- [4- (2-Fluoro-1-piperazinyl)] - 2-hydroxy-propoxy} -4-methoxymethyl-β-carboline-3-carbo-isopropyl ester. - xylic, m Mp 198-200 ° C.

Example 7

5- {3- [4- (4-Fluorobenzoyl) -piperidino] -2-methoxypropoxy) -4-methoxymethyl-β-carboxylic acid-3-carboxylic acid isopropyl ester

435 mg of 5- {3- [4- (4-fluorobenzoyl) -piperidino] -2-hydroxypropoxy} -4-methoxymethyl-4-carbonyl-3-carboxylic acid isopropyl ester is dissolved in 40 ml of ethylene glycol dimethyl ether, mixed with 20 mg of sodium hydride. (90%) and cooled in an ice bath to 0 ° C. To this reaction mixture was added dropwise 0.05 ml of methyl iodide, and the reaction mixture was stirred for 4 hours. After warming to room temperature, it was stirred for an additional 2 hours. After evaporation of the solvent, the residue is chromatographed on silica gel with methylene chloride / ethanol 100:50. 175 mg of 5- (3- [4- (4-fluorobenzoyl) -piperidino] -2-methoxypropoxy) -4-methoxymethyl isopropyl ester is obtained. -p-carboline-3-carboxylic acid, m.p. 137-139 ° C.

Claims (6)

PATENT CLAIMS 1. Alkoxy-substituted β-carboline derivatives of the general formula I in which * A denotes a straight or branched alkylene group s 1 to 5 carbon atoms, which may be substituted by hydroxy, 1 to 6 carbon alkoxy or 1 to 6 carbon alkanoyloxy, or - (CH ₂ ) _n -CO- (CH ₂ ) _m -, wherein: * »·. n and m are 1, 2 or 3, τ - '2 · - * R and R are the same or different and denote a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkyl group having 4 to 9 carbon atoms, a phenyl group, a phenylalkyl group having Or (C 1 -C 2) alkyl; R and R together with the nitrogen atom form a heterocycle of formula (a) -NB (a) wherein B represents a direct bond, an oxygen atom, a sulfur atom or a group = CH-R ^, = COH-R ^ or = NR ^ wherein r5 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms , C1 -C4 alkyl, C1 -C4 alkoxy, halogen, hydroxy, trifluoromethyl or -O-CF3 substituted by one to three times phenyl, benzyl, benzoyl, α-hydroxybenzyl, phenethyl , 2-oxo-2-phenethyl, 1-oxo-2-phenethyl or pyridine and Y represents an oxygen atom, a sulfur atom or a group = NH, R represents a hydrogen atom, a carboxyl group, a COO-alkyl group having 1 to 6 carbon atoms in the alkyl group, a CO-R1 group or, alternatively, one to three times an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group (C až-C skupinou), halogen, (C až-C alko) alkoxyalkyl, (C až-C až) alkyl, (C až-C alko) alkoxy, phenyl or amino-substituted (C a-C 12) aryl group atoms or heteroaryl, the alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a bicycloalkyl group having 7 to 9 carbon atoms, or an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms; C 1 -C 4 or amino substituted C 6 -C 12 monocyclic or bicyclic aryl; R &lt; ⁴ &gt; represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyalkyl group having 1 to 4 carbon atoms, even in an alkoxy group having 1 to 2 carbon atoms in the alkyl group, and R @ 1 denotes a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenylalkyl having 1 to 2 carbon atoms in an alkyl, an optionally substituted benzenesulfonyl group or an alkanesulfonyl group having 1 to 4 carbon atoms atoms, as well as their stereoisomers and salts. Alkoxy-substituted β-carboline derivatives according to claim 2 1 2 1, wherein R and R together with the nitrogen atom form a heterocycle of formula (a). An alkoxy-substituted β-carboline derivative according to claim hyl-O-carboline-3-carboxylic acid. A medicament based on alkoxy-substituted β-carboline derivatives according to claims 1 and 2. Use of alkoxy-substituted β-carboline derivatives according to claims 1 and 2 for the manufacture of medicaments. 6. A process for the preparation of alkoxy-substituted β-carboline derivatives according to claim 1, which comprises: a) a compound of formula II R HIM R &lt; 9 > wherein R &lt; 6 &gt; and R &lt; 6 &gt; are as defined above, is reacted with an amine of formula III X - A - N (lit) wherein R ¹ , R ² and A are each. the above meaning and ^m X denote & quot ^{; J} &apos; -J &quot; a leaving group, or b) a compound of the formula IV in which A, R ³ , R ^{4 * * * *} and R ^{9 are} as defined above and X represents a leaving group, is reacted with an amine of the formula V ^{R 1} HN (R) ^? _'Ϊ́ \ _r2' Wherein R and R are as defined above, ⁴ '⁴; Optionally, the R ⁹ substituent is then introduced or cleaved, or a physiologically acceptable salt is formed, or the physiologically acceptable salt is converted into the free compounds of formula I, or resolved by racemates.